Opiates play a major role in the management of pain, but not without problems. Side-effects are often limiting and their increased availability has led to major societal problems with their abuse. Most opioids used clinically act through the mu receptor, a G-protein-coupled receptor encoded by the Oprm gene. The wide range of clinical responses to a number of mu opioids raised the question of multiple mu receptor subtypes, a concept that has been confirmed with cloning studies. The mu opioid receptor (MOR-1) has a wide range of splice variants, with similar splicing patterns in mice, rats and humans. There are two groups of variants. One is comprised of full length 7 transmembrane domain receptors with 3' splicing, differing only at the tip of the intracellular C-terminus. The other set involve truncated variants generated from 5' splicing of unclear significance. We recently generated a series of opioid analgesics with unique pharmacological profiles and found that they act through a novel receptor target involving a truncated MOR-1 variant. The objective of this proposal is to further understand these MOR-1 splice variants. The first aim focuses upon the target for IBNtxA and the six transmembrane domain variants that appear to be a component using a variety of approaches. The second looks at single transmembrane domain variants and their role in morphine analgesia and tolerance while the third explores the effects of 3' splicing in two full length variants.